Osteoclasts are multinucleated cells of up to 400 .mu.m in diameter that resorb mineralized tissue, chiefly calcium phosphate, in vertebrates. They are actively motile cells that migrate along the surface of bone. They can bind to bone, secrete necessary acid and proteases and thereby cause the actual resorption of mineralized tissue from the bone.
More specifically, osteoclasts are believed to exist in at least two physiological states. In the secretory state, osteoclasts are flat, attach to the bone matrix via a tight attachment zone (sealing zone), become highly polarized, form a ruffled border, and secrete lysosomal enzymes and acid to resorb bone. The adhesion of osteoclasts to bone surfaces is an important initial step in bone resorption. In the migratory or motile state, the osteoclasts migrate across bone matrix and do not take part in resorption until they attach again to bone.
The current major bone diseases of public concern are osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget's disease, immobilization-induced osteopenia, loosening of bone prostheses and glucocorticoid treatment.
All these conditions are characterized by bone loss, resulting from an imbalance between bone resorption (breakdown) and bone formation, which continues throughout life at the rate of about 10% per year on the average. However, the rate of bone turnover differs from site to site, for example, it is higher in the trabecular bone of the vertebrae and the alveolar bone in the jaws than in the cortices of the long bones. The potential for bone loss is directly related to turnover and can amount to over 5% per year in vertebrae immediately following menopause, a condition which leads to increased fracture risk.
There are currently 20 million people with detectable fractures of the vertebrae due to osteoporosis in the United States. In addition, there are 250,000 hip fractures per year attributed to osteoporosis. This clinical situation is associated with a 12% mortality rate within the first two years, while 30% of the patients require nursing home care after the fracture.
Individuals suffering from all the conditions listed above would benefit from treatment with agents which inhibit bone resorption.
The literature discloses a variety of estrogen receptor modulators (termed "atypical estrogen agonists", "estrogen receptor mixed agonists/antagonists", "estrogen mimetics", "bone selective estrogens", "antiestrogens", etc.) which are useful in the treatment and prevention of diseases involving bone resorption. Representative examples may be found in the following: U.S. Pat. No. 3,274,213; U.S. Pat. No. 4,133,814; U.S. Pat. No. 4,230,862; U.S. Pat. No. 4,323,707; U.S. Pat. No. 4,380,635; U.S. Pat. No. 4,400,543; U.S. Pat. No. 4,418,068; U.S. Pat. No. 4,536,516; U.S. Pat. No. 5,254,594; EPO Patent Pub. No. 0,062,503; EPO Patent Pub. No. 0,054,168; EPO Patent Pub. No. 0,260,066; EPO Patent Pub. No. 0,470,310; EPO Patent Pub. No. 0,651,998-0,652,005; EPO Patent Pub. No. 0,657,162; EPO Patent Pub. No. 0,659,411-0,659,429; EPO Patent Pub. No. 0,662,325; EPO Patent Pub. No. 0,663,209; EPO Patent Pub. No. 0,664,121-0,664,126; EPO Patent Pub. No. 0,665,015; EPO Patent Pub. No. 0,668,075; EPO Patent Pub. No. 0,670,162; EPO Patent Pub. No. 0,674,903; EPO Patent Pub. No. 0,683,170; EPO Patent Pub. No. 0,703,228; EPO Patent Pub. No. 0,716,855; EPO Patent Pub. No. 0,729,951; EPO Patent Pub. No. 0,729,956; EPO Patent Pub. No. 0,731,093; EPO Patent Pub. No. 0,731,098; EPO Patent Pub. No. 0,731,100; EPO Patent Pub. No. 0,733,620; EPO Patent Pub. No. 0,747,054; German Patent Pub. No. DE 2,329,201; Japan Patent Pub. No. 5,032,579; PCT Patent Pub. No. 96/09039; PCT Patent Pub. No. 96/09040; PCT Patent Pub. No. 96/09041; PCT Patent Pub. No. 96/09045; PCT Patent Pub. No. 96/09050; PCT Patent Pub. No. 96/09051; PCT Patent Pub. No. 96/09052; PCT Patent Pub. No. 96/21441; PCT Patent Pub. No. 96/22771; PCT Patent Pub. No. 96/26727; PCT Patent Pub. No. 96/26935; PCT Patent Pub. No. 96/32937; PCT Patent Pub. No. 96/39833; and Jones, et al., J. Med. Chem., 27 1057-1066 (1984). The preparation of estrogen receptor modulators is well known in the art. Representative examples may be found in the above mentioned references which disclose the compounds as being useful for the treatment of bone diseases, in particular, as inhibitors of bone resorption.
The treatment of osteoporosis with calcitonin, alone and in combination with human growth hormone ("GH") was examined by Aloia, et al., Metabolism, 34(2) 124-129 (1985). This publication ascribes no benefit in the treatment of osteoporosis from combining calcitonin therapy with the administration of growth hormone and noted that the addition of growth hormone to calcitonin therapy appeared to have a deleterious effect on cortical bone mass. The effects of growth hormone itself in the treatment of osteoporosis was studied by Aloia, et al., J. Clin. Endocrinol. Metab., 54, 992-999 (1976). This publication noted that under the conditions of the study, growth hormone administration did not result in an increment in skeletal mass. The effects of growth hormone on human bone biology have been reviewed by Inzucchi, et al. J. Clin. Endocrinol. Metab., 79(3), 691-694 (1994). General reviews of human growth hormone also discuss the role of growth hormone on bone (Strobl, et al Pharmacol. Reviews, 46(1), 1-34 (1994); Chipman, J. Pediatric Encocrinol., 6(3-4), 325-328 (1993)). Bone turnover and bone mineral density in young adult patients with panhypopituitarism following long-term growth hormone therapy was examined by Balducci, et al. Eur. J. Endocrinol., 132(1), 42-46 (January 1995). Also, the effect of growth hormone replacement on bone has been examined in boys with and without classic growth hormone deficiency (Zadik, et al., J. Pediatrics, 125(2), 189-195 (1994)) and in adults with adult onset growth hormone deficiency (Holmes, et al., Clin. Endocrinol., 42, 627-633 (1995)). There is a difference in the literature between effects in GH-deficient children, where improvement with GH is seen, and in adults, where most reports show both, increased bone resorption and formation, but no positive balance.
Certain non-peptidal growth hormone secretagogues are known to stimulate the pituitary gland to increase its secretion of growth hormone with utility in growth hormone deficient children and adults, in severe burn victims, in the treatment of Turners syndrome, for reversing the adverse effects of glucocorticoid treatment, for treating muscle and exercise tolerance deficiencies in growth hormone deficient adults, and for the treatment of osteoporosis. Certain compounds have been developed which stimulate the release of endogenous growth hormone. Peptides which are known to stimulate the release of endogenous growth hormone include growth hormone releasing hormone, the growth hormone releasing peptides GHRP-6 and GHRP-1 (described in U.S. Pat. No. 4,411,890, PCT Patent Pub. No. WO 89/07110, and PCT Patent Pub. No. WO 89/07111) and GHRP-2 (described in PCT Patent Pub. No. WO 93/04081), as well as hexarelin (J. Endocrinol Invest., 15(Suppl 4), 45 (1992)). Other compounds possessing growth hormone secretagogue activity are disclosed in the following: U.S. Pat. No. 3,239,345; U.S. Pat. No. 4,036,979; U.S. Pat. No. 4,411,890; U.S. Pat. No. 5,206,235; U.S. Pat. No. 5,283,241; U.S. Pat. No. 5,284,841; U.S. Pat. No. 5,310,737; U.S. Pat. No. 5,317,017; U.S. Pat. No. 5,374,721; U.S. Pat. No. 5,430,144; U.S. Pat. No. 5,434,261; U.S. Pat. No. 5,438,136; U.S. Pat. No. 5,494,919; U.S. Pat. No. 5,494,920; U.S. Pat. No. 5,492,916; U.S. Pat. No. 5,536,716; EPO Patent Pub. No. 0,144,230; EPO Patent Pub. No. 0,513,974; PCT Patent Pub. No. WO 94/07486; PCT Patent Pub. No. WO 94/08583; PCT Patent Pub. No. WO 94/11012; PCT Patent Pub. No. WO 94/13696; PCT Patent Pub. No. WO 94/19367; PCT Patent Pub. No. WO 95/03289; PCT Patent Pub. No. WO 95/03290; PCT Patent Pub. No. WO 95/09633; PCT Patent Pub. No. WO 95/11029; PCT Patent Pub. No. WO 95/12598; PCT Patent Pub. No. WO 95/13069; PCT Patent Pub. No. WO 95/14666; PCT Patent Pub. No. WO 95/16675; PCT Patent Pub. No. WO 95/16692; PCT Patent Pub. No. WO 95/17422; PCT Patent Pub. No. WO 95/17423; PCT Patent Pub. No. WO 95/34311; PCT Patent Pub. No. WO 96/02530; PCT Patent Pub. No. WO 96/05195; PCT Patent Pub. No. WO 96/15148; PCT Patent Pub. No. WO 96/22782; PCT Patent Pub. No. WO 96/22997; PCT Patent Pub. No. WO 96/24580; PCT Patent Pub. No. WO 96/24587; PCT Patent Pub. No. WO 96/35713; PCT Patent Pub. No. WO 96/38471; PCT Patent Pub. No. WO 97/00894; PCT Patent Pub. No. WO 97/06803; PCT Patent Pub. No. WO 97/07117; Science, 260, 1640-1643 (Jun. 11, 1993); Ann. Rep. Med. Chem., 28,177-186 (1993); Bioorg. Med. Chem. Ltrs., 4(22),2709-2714 (1994); and Proc. Natl. Acad. Sci. USA 92 7001-7005 (July 1995).